In 1978, it was reported for the first time that antisense molecules inhibited infection by influenza virus. Since then, reports have been issued that antisense molecules also inhibited oncogene expression and AIDS infection. Since antisense oligonucleotides specifically control the expression of undesirable genes, they have become one of the most promising fields as medicines in recent years.
The antisense method is based on the concept of controlling a series of information flow steps of the so-called central dogma, DNA→mRNA→protein, by use of an antisense oligonucleotide.
When a natural type oligonucleotide was applied as an antisense molecule to this method, however, problems arose such that it underwent hydrolysis by enzymes present in vivo, and its cell membrane permeation was not high. To resolve these problems, numerous nucleic acid derivatives have been synthesized, and have been extensively studied. For example, phosphorothioates having an oxygen atom on a phosphorus atom substituted by a sulfur atom, and methylphosphonates having an oxygen atom on a phosphorus atom substituted by a methyl group were synthesized. Recently, the derivatives having the phosphorus atom also substituted by a carbon atom, and molecules having ribose converted to an acyclic skeleton have also been synthesized (F. Eckstein et al., Biochem., 18, 592 (1979), P. S. Miller et al., Nucleic Acids Res., 11, 5189 (1983), P. Herdewijn et al., J. Chem. Soc. Perkin Trans. 1, 1567 (1993), P. E. Nielsen et al., Science, 254, 1497 (1991)).
However, none of these derivatives are fully satisfactory in in vivo stability, ease of synthesis of oligonucleotides, and so on.
In the light of the above-described conventional technologies, provision is desired of nucleotide analogues which have high cell membrane permeation under in vivo conditions, which are minimally hydrolyzed with enzymes, whose synthesis is easy, and which are useful for the antisense method, the antigene method, RNAi, and the decoy method.